Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase

Mol Med. 2002 Jan;8(1):1-8.


Background: Implantation of foreign materials into mice and humans has been noted to result in the appearance of soft tissue sarcomas at the site of implantation. These materials include metal replacement joints and Dacron vascular grafts. In addition, occupational exposure to nickel has been shown to result in an increased risk of carcinogenesis. The molecular mechanisms of foreign body-induced carcinogenesis are not fully understood.

Materials and methods: In order to gain insight into these mechanisms, we implanted nickel sulfide into wild type C57BL/6 mice as well as a mouse heterozygous for the tumor suppressor gene, p53. Malignant fibrous histiocytomas arose in all mice, and we have characterized the profile of tumor suppressor genes and signal transduction pathways altered in these cells.

Results: All tumors demonstrated hypermethylation of the tumor suppressor gene p16, as well as activation of the mitogen activated protein kinase (MAP kinase) signaling pathway. This knowledge may be beneficial in the prevention and treatment of tumors caused by foreign body implantation.

Conclusions: Oxidative stress induced by nickel sulfide appears to cause loss of p16 and activation of MAP kinase signaling. These findings support the hypothesis of synergistic interactions between MAP kinase activation and p16 loss in carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinogens / pharmacology
  • Carcinogens / toxicity*
  • CpG Islands
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Methylation / drug effects*
  • Drug Implants
  • Enzyme Activation / drug effects
  • Gene Expression Regulation / drug effects
  • Genes, p16 / drug effects*
  • Genes, p53
  • Genes, ras
  • Hindlimb
  • Histiocytoma, Benign Fibrous / chemically induced*
  • Histiocytoma, Benign Fibrous / enzymology
  • Histiocytoma, Benign Fibrous / genetics
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle Neoplasms / chemically induced*
  • Muscle Neoplasms / enzymology
  • Muscle Neoplasms / genetics
  • Mutagenesis
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Nickel / pharmacology
  • Nickel / toxicity*
  • Oxidative Stress
  • Polymerase Chain Reaction
  • Reactive Oxygen Species / pharmacology
  • Reactive Oxygen Species / toxicity*
  • Tumor Suppressor Protein p14ARF / genetics


  • Carcinogens
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Drug Implants
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p14ARF
  • Nickel
  • Mitogen-Activated Protein Kinases
  • nickel sulfide